Acetonides or derivatives of 1,3-dioxolane are cyclic ketals which are prepared for example from 1,2-diols, ketones or aldehydes. It is known in the prior art that acid catalysts assist and/or enable this reaction. The cyclic ketals are synthetically valuable compounds which may be used to good effect on account of their special properties.
In the special case of the 1,3-dioxolan-2-ones, for example the carboxylic acid function structurally contained therein may be activated to assist acylation reactions. As in this case possibly volatile ketones or aldehydes escape as a by-product of the reaction, the reaction equilibrium is favourably influenced towards the acylation of an alcohol, for example (cf. “A new Synthesis of alpha-Hydroxycarboxylates and 2-Hydroxybenzoates”, Khalaj, Ali; Aboofazaeli, Rem; Iranian Journal of Chemistry & Chemical Engineering (1997), 16(1), 1-3). 1,3-Dioxolan-2-ones, by cyclisation of an alpha-hydroxycarboxylic acid, combine the protection of their individual functionalities and convert them into an ether and a lactone functionality in each case. This sometimes decisively increases the stability of the whole molecule. Depending on the pattern of substituents and the intended reaction, either the stabilising or the activating effect in the molecule may dominate and be exploited.
It is possible to use ketones and aldehydes as the protective group for alpha-hydroxycarboxylic acids, as the former can be cleaved again from the 1,3-dioxolan-2-ones under defined mild conditions (acidic or basic).
1,3-dioxolan-2-ones are also known starting materials for preparing alpha-hydroxycarboxylic acid esters and alpha-hydroxycarboxylic acid amides (“Synthesis of alpha-Hydroxycarboxamides from Acetonids of alpha-Hydroxycarboxylicacids and Primary Amines”, Khalaj, A.; Nahid, E., Synthesis (1985), (12), 1153-1155).
Methods of synthesis for preparing dioxolanes are described for example in “Synthesis and Configuration of Aryl-Substituted 1,3-Dioxolan-4-ones”, Samoiloski, N. A.; Lapkin, L I.; Proshutinski, V. I.; Krutko, N. E.; Zhurnal Organicheskoi Khimii (1973), 9(6), 1145-1148. The cleaving of 1,3-dioxolan-2-ones to form the 2-hydroxycarboxylic acid ester has already been described in the literature (cf. “A new Synthesis of alpha-Hydroxycarboxylates and 2-Hydroxybenzoates”, Khalaj, Ali; Aboofazaeli, Reza; Iranian Journal of Chemistry & Chemical Engineering (1997), 16(1), 1-3). The cleaving may be carried out with acid or base catalysis.
Furthermore, numerous 2-hydroxycarboxylic acid esters are known for their pharmacological activity, with the result that there is a constant search for ways of developing better and simpler methods of synthesising them. It is also known that alpha-hydroxycarboxylic acid esters themselves may be used as precursors for preparing other pharmacologically active compounds. One example of this is the pharmacologically effective 2,2-diarylglycolic acid esters of aminoalcohols, such as e.g. the tiotropium salt having the chemical formula:
wherein X− denotes an anion, preferably bromide. Tiotropium salts are categorised as anticholinergics. In the prior art tiotropium bromide in particular is described as a highly potent anticholinergic. Tiotropium bromide is known for example from EP 418 716 A1.
All the preparation methods for acetonides/dioxolanones published hitherto use strong acids as catalysts. A problem of the known processes is therefore that acid-sensitive compounds cannot be obtained using the known conventional acid-catalysed methods of synthesis. This restricts the use of the reaction to acid-stable raw materials and target molecules. In a reaction with thienyl-substituted glycolic acid, for example, conventional methods of preparation cannot be used owing to the instability of this component. A great many side reactions are obtained, in some cases with the formation of coloured components which contaminate the end product and incur considerable expense in purification.
The problem on which the present invention is based is therefore to provide an improved mild, technically practicable method of synthesis which provides a way of synthesising 1,3-dioxolanes or 2-hydroxycarboxylic acid esters that have temperature- and/or acid-sensitive functionalities.